N - (4-(beta-&lt;2-methoxy-5-chloro-benzamido&gt;-ethyl) - benzenesulfonyl)-n&#39;-cyclopentyl-urea and process for its manufacture

ABSTRACT

N-(14 -B-&lt;2-METHOXY-5-CHLORO-BENZAMIDOS&gt;-ETHYL)BENZENESULFONYL)-N&#39;&#39;-CYCLOPENTYL -UREA OF THE FORMULA   (CYCLOPENTYL)-NH-CO-NH-SO2-(1,4-PHENYLENE)-(CH2)2-NH-CO-   (5-CL-1,3-PHENYLENE)-O-CH3   HAVING A LONG-LASTING AND STRONG HYPOGLYCEMIC ACTION IN THE TREATMENT OF DIABETES MELLITUS AND A PROCESS FOR ITS MANUFACTURE.

Patented fonyl-isourea ester, benzensuelfonyl-parabanic acid or3,754,030 benznesulfonyl-haloformic acid amidine is hydrolized,

N [4-(5- 2-METHOXY-5-CHLORO-BENZAMIDO o ETHYL)BENZENESULFONYL]-N-CYCLOPENT- r a compound of the mmula ULRU$EA ANDPROCESS FOR ITS MANUFAC- 5 Cl Helmut Weber, Frankfurt am Main, WalterAumullcr,

and Karl Muth, Kclkheim, Taunus, and Rudi Weyer, NH NH Frankfurt amMain, Germany, assignors to Farbwerke U Hoechst Aktiengesellschaftvormals Meister Lucius & 0H: Bruuing, Frankfurt am Main, Germany NoDrawing. Filed Feb. 11, 1970, Ser. No. 10,659

Cl priority, application y, Feb. 1969 or a parabamc acid derivativethereof or a compound P 19 09 272.9 of the formula Int. Cl. C07c 127/0001 U.S. Cl. 260-553 DA 1 Claim 15 ABSTRACT OF THE DISCLOSURE N [4 ([3-2-methoxy-5-ch1oro-benzamido -ethyl)- Ubenzenesulfonyl]-N'-cyclopentyl-urea of the formula -oO-NH-Cm-Cm-Q-Sm-NH-C ONH- having a long-lasting and strong hypoglycemicaction in wherein U stands for oxygen-lower-alkyl, sulfur-lowerthetreatment of diabetes mellitus and a process for its lkyl or halogen(preferably chlorine), is saponified or manufacture. water is added in acorrespondingly substituted carbodiimide,

The present invention relates to N-[4-(fi- 2-methoxya wrrep0nding1ysubstituted benzenesulfonyl- 5 chloro-benzamido-ethyl)-bei1zenesulfony1]-N-cyclothlourea orthlobenzamldo-alkyl-benzene-sulfonyl-urea, pentyl-urea of the formulathe sulfur atom is replaced by an oxygen atom;

CONHCHzCHz-S0 NHCO-NH which in the free form or in the form of its saltshas blood (d) a correspondingly substituted benzenesulfinyl-urea orsugar lowering properties and is distinguished by a strongbenzene-sulfenyl-urea is oxidized, and long-lasting hypoglycemic action.(e) the group The present invention furthermore relates to processes 01for preparing this benzenesulfonyl-urea, wherein (a) abenzenesulfonyl-isocyanate, a benzenesulfonyl-car- Q0- bamic acid ester,a benzenesulfonyl-thiolcarbamic acid ester, a benzenesulfonyl-urea, abenzenesulfonyl-semicarbazide or a benzenesulfonyl-semicarbazone which 0t 1S subsmuted m parwposltlon by the group 1s introduced by acylation 1none r more s eps into N- [4 S-aminoethyl) -b enzenesulfonyl]-N'-cyclopentylc1 urea of the formula is reacted with cyclopentyl-amineor a salt thereof, or a correspondingly Substituted beflzeneslllffmylhalide 4 (B y' h10I'O-b6lJZamld0 -ethyl)-benis reacted withcyclopentyl-urea or an alkali metal salt lf id f the f l thereof or acorrespondingly substituted benzenesul- O1 finic acid halide or, in thepresence of an acid condensation agent, even a correspondinglysubstituted benzenesulfinic acid or an alkali metal salt thereof is(JO-NH CHPCHFQSOPNH reacted with N-cyclopentyl-N'-hydroxy-urea,

CH3 and, if desired, the reaction product obtained is treated or a saltthereof is reacted with a cyclopentyl-isocya- Wlth an alkallfle agentfor Salt fflrmatloflnate, carbamic acid ester, thioalcarbamic acidester, The aforesaid benzenesulfonyl-carbamic acid esters or c bamicacid halid o u benzene-sulfonyl-thiolcarbamic acid esters may contain in(b) a correspondingly substituted benzenesulfonyl-isourea the alcoholiccomponent an alkyl group or an aryl group ether,benzenesulfonyl-isothiourea ether, benzenesulor even a heterocyclicradical. Since this radical is split off 3 during the reaction, itschemical constitution has no influence on the nature of the finalproduct and may, there fore, be varied Within wide limits. The sameapplies to the cyclopentyl-amine-substituted carbamic acid esters andthe corresponding thiolcarbamic acid esters.

As carbamic acid halide, the chloride is preferably used.

The benzenesulfonyl-ureas used as starting materials in the .process ofthe present invention may be unsubstituted at the side of the ureamolecule opposite to the sulfonyl group or may be monoor, especially,di-substituted. Since these substituents are split off during thereaction with the amines, their nature can be varied within wide limits.In addition to benzenesulfonyl-ureas which carry alkyl, aryl, acyl orheterocyclic substituents, there may also be usedbenzenesulfonylcarbamoyl-imidazoles and similar compounds orbis-(benzenesulfonyl)-ureas which may carry at one of the nitrogen atomsa further substituent, for example a methyl group. For example, suchbis- (benzene-sulfonyD-ureas or also N-benzene-sulfonyl-N'- acyl-ureasmay be treated with cyclopentylamine and the salts obtained may beheated to elevated temperatures, especially to a temperature above 100C.

Furthermore, it is possible to start from cyclopentylurea or from acyclopentyl-ureas which is monoor, especially, disubstituted at the freenitrogen atom, and to react it with ooNn om=oH.-somm As such startingmaterials, there may be used for example N-cyclopentyl-urea, thecorresponding N-acetyl, N'-nitro, N'-cyclopentyl, N',N'-diphenyl- (inwhich case the two phenyl radicals may also be substituted or be linkedwith each other either directly or also by means of a bridge membersuch, for example, as -CH -NH, O or --S), '-methyl-N'-phenyl,N',N'-dicyclohexyl-ureas as well as cyclopentyl-carbamoyl-imidazoles,-pyrazoles or -triazoles.

The hydrolysis of the benzenesulfonyl-parabanic acids,benzensulfonyl-isourea ethers, benzenesulfonyl-isothiourea ethers,benzenesulfonyl-ioursea esters or benzenesulfonylhaloformic acidamidines mentioned as starting substances is suitably carried out in analkaline medium. Isourea ethers and isourea esters may also behydrolized successfully in the acid medium.

The replacement of the sulfur atom in the correspondingly substitutedbenzenesulfonyl-thioureas by an oxygen atom can be effected in knownmanner, for example, with the aid of oxides or salts of heavy metals orwith the use of oxidizing agents such, for example, as hydrogenperoxide, sodium peroxide, nitrous acid or permanganates.

The thioureas may also be desulfnrized by treatment with phosgene orphosphorus pentachloride. The chloroformic acid amidines orchlorofor-mic acid carbodiimi-des obtained as intermediates may beconverted into the henzenesulfonyl-ureas by suitable measures such, forexample, as by saponification or addition of water.

The acylation of theN-[4(fi-aminoethyD-benzenesulfonyl]-N-cyclopentyl-urea may be carriedout either in one step, for example by the reaction of correspondinglysubstituted benzoic acid halides, or it may be effected in severalsteps. As an example of the numerous possibilities of a stepwiseacylation, there may be mentioned the reaction ofaminoethyl-benzenesulfonyl-ureas with Z-methoxy-benzoyl chloride and thesubsequent introduction of a chlorine atom into the benzene nucleus ofthe benzamido group.

The oxidation of the benzenesulfinyl-ureas or benzenesulfenyl-ureas maybe carried out with the aid of known oxidizing agents, for examplepotassium permanganate.

As regards the reaction conditions, the methods of carrying out theprocess of the invention may, in general, be varied within wide limitsand may be adapted to each individual cases. For example, the reactionsmay be carried out in the presence or in the absence of solvents, atroom temperature or at an elevated temperature.

Depending on the nature of the starting substances, one or other of theaforesaid methods may, in some cases, provide a desired individualbenzenesulfonyl-urea only in a small yield or may be inappropriate forits synthesis. In such comparatively rare cases, the expert will have nodifiiculty in synthesizing the desired product according to-one of theother methods of the process described.

The starting materials are prepared by methods that are generally known.For example, substituted benzenesulfonamides used as starting substancesmay be obtained by the reaction of the corresponding benzene compoundswith chlorosulfonic acid and subsequently with ammonia or by acylationof paminoethyl-benzenesulfonamide with corresponding acid chlorides. Thebenzenesulfonylurethanes or benzcnesulfonyl-ureas used as startingmaterials may be prepared, for example, from the correspondingbenzenesulfonamides and haloformic acid alkyl esters or potassiumcyanate (KOCN). Benzenesulfinyl-ureas or benzenesulfenyl-ureas may beobtained by the condensation of the corresponding sulfinyl chlorides orsulfenyl chlorides with ureas.

The hypoglycemic action of the afore-described benzenesulfonyl-urea canbe ascertained by administering it in the form of the sodium salt in adose of 10 rug/kg. of body weight to normally fed rabbits anddetermining the blood sugar level according to the known method ofHagedorn-Jensen or by means of an auto-analyzer for a prolonged periodof time.

Thus, it has been found that N-[4-(,B- 2-methoxy-5- chloro benzamido-ethyl) bcnzenesulfonyl]-N'-cyclopentyl-urea (I) causes the lowering ofthe blood sugar level as indicated in the following table.

For comparison, the lowering of the blood sugar level produced by theknown N-[4-(5- 2-methoxy-5-chlorobenzamido ethyl) benzenesulfonyl]N-cyclohexylurea (II) is also indicated in this table.

TABLE [Lowering o! the blood sugar level in rabbits, in percents alteror administration of 10 mg./kg.]

After- 1 3 6 24 8 72 96 hr. hrs. hrs. hrs. hrs. hrs. hrs. hrs.

CompoundI 18 39 36 45 50 41 27 0 Compound II 19 23 28 13 0 -t Thebenzzeuesulfonyl-urea of the present invention is preferably used forthe manufacture of pharmaceutical preparations suitable for oraladministration and for the lowering of the blood sugar level in thetreatment of diabetes mellitus, for which purpose it may be used as suchor in the form of its physiologically tolerable salts or in the presenceof substances which cause salt formation. For the formation of salts,there may be used, for example, alkaline agents such as alkali metaloralkaline earth metal hydroxides, carbonates or bi carbonates; these arecommonly used in the pharmaceutical industry to form physiologicallytolerable salts.

The present invention therefore also provides pharmaceuticalpreparations that have hypoglycemic action and are suitable for oraladministration in the treatment of diabetes mellitus, which preparationshave preferably the form of tablets and contain as the active ingredientthe benzenesulfonyl-urea of the invention or a salt thereof in admixtureor conjunction with pharmaceutically suitable carriers such as talc,starch, lactose, tragacanth or magnesium stearate.

Such a pharmaceutical preparation, for example a tablet or a powder,containing the benzenesulfonyl-urea of the invention or aphysiologically tolerable salt thereof as the active substance, with orwithout one or more of the aforementioned carriers, is advantageouslybrought into a suitable dosage unit form. The dose chosen should complywith the activity of the benzenesulfonyl-urea used and with the desiredeflect. Advantageously, the dosage per unit amounts to about 0.5 to 100mg., preferably 2 to mg., but considerably higher or lower dosage unitsmay also be used, which, where required, are divided or multiplied priorto their administration.

The following examples serve to illustrate some variants of the process,which may be used for the synthesis of the benzenesulfonyl-ureas of theinvention.

EXAMPLE 1 N-[4-(fi- 2-methoxy-5-chloro-benzamido -ethyl)-benzenesulfonyl]-N-cyclopentyl-urea 2.45 g. of N-[4-(fl- 2-methoxy 5chloro-benzamido -ethyl)-benzenesulfonyl] phenylurethane (obtained from4-[5-(2 methoxy 5 chlorobenzamido)-ethyl]- benzenesulfonamide andchloroformic acid phenyl ester) were refluxed for 2 hours with 0.43 g.of cyclopentylamine in 30 m1. of dioxane. After dilution with water andacidification with dilute hydrochloric acid a precipitate was obtainedwhich was treated with 0.5% ammonia. The aqueous alkaline solution wasacidified and the precipitate obtained was recrystallized from methanol.N-[4-(/8- 2 methoxy 5 chloro-benzamido ethyl)-benzenesulfonyl] Ncyclopentyl-urea, melting point 184-195 C., was obtained.

EXAMPLE 2 N-[4-( 3- 2-methoxy-S-chloro-benzamido -ethyl)-benzensulfonyl] -N'-cyclopentyl-urea 4.26 g. of N-[4-(18- 2 methoxy 5chloro-benzamido -ethyl)-benzenesulfonyl] methylurethane were heated forone and a half hours with 1.5 g. of cyclopentyl-amine acetate in 100 ml.of dioxane, using a descending condenser.

After addition of water and recrystallization of the product obtainedfrom methanol N-[4-(,8 2-methoxy- 5 chloro benzamido ethyl)benzenesulfonyl]- -cyclopentyl-urea, melting point 184-185 C., wasobtained in a very good yield.

EXAMPLE 3 N-[4-(l3- 2-methoxy-5-chloro-benzamido -ethyl)-benzenesulfonyl]-N-cyclopentyl-urea A mixture of 10.3 g. of N-[4-(/3- 2methoxy-5- chloro benzamido ethyl) benzenesulfonyl] urea (M.P. 171173C.), 300 ml. of toluene, 30 ml. of glycolmonomethyl ether, 1.65 g. ofglacial acetic acid and 2.4 g. of cyclopentyl-amine was refluxed for 5hours. Subsequently, the mixture was concentrated in vacuo and theresidue was treated with alcohol. N-[4-(;3- 2- methoxy 5 chlorobenzamido ethyl)-benzenesulfonyl] N cyclopentyl-urea obtained as a rawproduct was separated by suction-filtration and recrystallized frommethanol. Melting point 184-185 C.

EXAMPLE 4 N- [4- )3- 2-methoxy-S-chloro-benzamido -ethyl)benzenesulfonyl]-N-cyclopentyl-urea 4.9 g. of N-[4-(fi-2-methoxy-5-chloro-benzamido ethyl)-benzenesulfonyl] N phenyl-urea (M.P.193 195 C.), 100 ml. of dioxane and 0.85 g. of cyclopentyl-amine wererefluxed for 1 hour.

The clear solution was subsequently concentrated in vacuo and theresidue obtained was treated with about 0.5%-ammonia. Afterclarification of the solution by 6 filtration it was acidified. Theprecipitate of N-[4-(p- 2-methoxy 5 chloro-benzamido-ethyl)-benzenesulfonyl] N cyclopentyl-urea obtained was isolated bysuction-filtration and dried. After recrystallization from methanol aproduct was obtained having the melting point of 184185 C.

EXAMPLE 5 N-[4-(fi- 2-methoxy-'5-chloro-benzamido -ethyl)-benzenesulfonyl] -N'-cyclopentyl-urea 2.3 g. of N-[4-(fi-2-methoxy-5-chloro-benzamido ethyl)-benzenesulfonyl] N acetyl-urea (M.P.208 C. with decomposition) and 0.43 g. of cyclopentyl-amine werecarefully mixed. Upon heating, the cyclopentylamine salt of N-[4-(13 2methoxy 5 chloro-benzamido ethyl) benzenesulfonyl] N acetyl-urea wasformed. The salt was heated in an Erlenmeyer flask for 45 minutes to C.in an oil bath. After several minutes the salt melted to form a clearmelt.

The melt was cooled, treated with aqueous 0.5%- ammonia while heating onthe steam bath, then filtered and the filtrate was acidified. Theprecipitated crystals were separated by suction-filtration and taken uponce more in 0.5% ammonia.

Upon acidification of the filtrate, a crystalline precipitate of N-[4(;8- 2-methoxy 5 chloro-benzamido ethyl)-benzenesulfonyl] Ncyclopentyl-urea was obtained, separated by suction-filtration anddried. After recrystallization from methanol the substance was found tomelt at 183-184 C.

EXAMPLE 6 N-[4&5- 2-methoxy-5-chloro-benzamido -ethyl)-benzenesulfonyl]-N-cyclopentyl-urea 6.5 g. of sodium salt of 4-(fl 2methoxy-S-chlorobenzamido -ethyl) benzenesulfonamide were refluxed for 3hours with 3.9 g. of diphenylcarbamic acid chloride in 60 ml. oftoluene. The crude N-[4-(fl- 2-methoxy-5- chloro benzamido ethyl)benzenesulfonyl]-N',N'- diphenyl-urea obtained was suction-filtered,suspended in dioxane and, after addition of 1 g. of acetic acid and 1.6g. of cyclopentyl-amine, the substance was refluxed for 1 /2 hours.After acidification with dilute hydrochloric acid the precipitate wasseparated by suction-filtration and treated with 0.5%-ammonia. Theaqueous alkaline solution was acidified and the crystals wererecrystallized from methanol. N-[4 S- 2 methoxy 5 chlorobenzamido ethyl)benzenesulfonyl] N cyclopentyl-urea was obtained having a melting pointof 182- 184 C.

EXAMPLE 7 N-[4-(13- 2-methoxy-5-chloro-benza.mido -ethyl)-benzenesulfonyl] -N'-cyclopentyl-urea 0.95 g. of N,N' bis [4- (pl-2-methoxy 5 chlorobenzamido -ethyl) benzenesulfonyl]-urea (M.P. 183- 185C.) were suspended in 30 ml. of dioxane. 0.107 g. of cyclopentyl-aminewere added and the whole was refluxed for 1 hour. After concentration ofthe clear solution obtained the residue was treated with 0.5 aqueousammonia, the 4 3 2 methoxy 5 chloro-benzamido -ethyl)-benzenesulfonamideformed was separated by filtration and acidified. A crystallineprecipitate of N- [4-(;8- 2 methoxy 5 chloro benzamido ethyl)-benzenesulfonyl] N cyclopentyl-urea was obtained, isolated bysuction-filtration, dried and recrystallized from methanol. Meltingpoint 182184 C.

EXAMPLE 8 N- [4- (B- 2-methoxy-5-chloro-benzamido -ethyl)benzenesulfonyl] .-N'-cyclop entyl-urea 4.95 g. of 4-[4-({3-2-methoxy-5-chloro-benzamido ethyl) benzenesulfonyl]1,1-pentamethylene-semicarbazide, melting point 165l67 C., 50 ml. ofdioxane and 0.85 g. of cyclopentylamine were refluxed for 45 minutes.The solution obtained was concentrated in vacuo and the residue wastaken up in about 0.5 %-aqueous ammonia. The solution was filtered andthe filtrate was acidified. A crystalline precipitate of N-[4 (p-2-methoxy-5-chlorobenzamido ethyl) benzenesulfonyl]-N-cyclopentylureawas obtained, separated by suction-filtration and dried. Afterrecrystallization from methanol the substance was found to melt at183-185 C.

EXAMPLE 9 N-[4-(,8 2-methoxy-5-chloro-benzamido -ethyl)-benzenesulfonyl]N'-cyclopentyl-urea 1.8 g. of 4 [4-(5-2-methoxy-5-chloro-benzamido ethyl) benzenesulfonyl] cyclooctanonesemicarbazone, 50 ml. of dioxane and 0.29 g. of cyclopentyl-amine wererefluxed for 1 hour. The clear solution was concentrated in vacuo andthe residue obtained was treated with about 0.5 %-aqueous ammonia. Afterfiltration the filtrate was acidified. A crystalline precipitate ofN-[4-(fl 2-methoxy 5 chlorobenzamido -ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea was obtained, separated by suction-filtration, driedand recrystallized from methanol. The melting point of the substance was182184 C.

EXAMPLE N-[4-(fl- 2-methoxy-5-chloro-benzamido -ethyl)- benzenesulfonyl]N'-cyclopenty1-urea 7.5 g. of 4 (B Z-methoxy-S-chloro-benzamidoethyl)-benzene-sulfonamide and 5.6 g. of ground potassium carbonate weresuspended in 150 ml. of acetone and refluxed for 3 hours. Subsequently,2.3 g. of cyclopentylisocyanate (prepared by reaction ofcyclopentylaminehydrochloride with phosgene, boiling point 55 C. under apressure of 35 mm. mercury) were added thereto and the whole was heatedfor another 5 hours. The precipitate formed was separated bysuction-filtration, suspended in water and acidified with dilutehydrochloric acid. After suction-filtration, N [4-(,8-2-meth0xy-5-chl0r0-benzamido -ethyl)-benzene-sulfonyl]-N-cyclopentyl-urea was obtained which after recrystallization frommethanol was found to melt at 184-185 C.

EXAMPLE 11 N- [4- ,6- 2-methoxy-5-chloro-benzamido -ethyl benzenesulfonyl [-N'-cyclopentyl-urea 3.9 g. of sodium salt of 4-(ti-2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonamide and 4.1 g. of N-cyclopentyl-carbamic acid phenyl ester (prepared from chloroformic acidphenyl ester and cyclopentyl-amine) were dissolved in 100 ml. ofdimethylformamide. The solution was heated to 110 C. for 45 minutes,then allowed to cool and poured in about 0.5%-aqueous ammonia. Theundissolved substance was separated by filtration and the filtrate wasacidified. The crystallized precipitate of N- [4- (13-2-methoxy-5-chlorobenzamido -ethyl)- benzenesulfonyl]-N-cyclopentyl-ureawhich had precipitated was separated by suction-filtration, washed anddried. After recrystallization from methanol the substance was found tomelt at 182-l84 C.

EXAMPLE 12 N- [4-(fi- 2-methoxy-S-chloro-benzamido -ethyl)-benzenesulfonyl] -N-cyclopentyl-urea 3.9 g. of sodium salt of 4 (,9-2-methoxy-5-chlorobenzamido ethyl)-benzenesulfonamide and 3.84 g. ofcyclopentyl-urea (M.P. 196-197" C.) were well mixed in a mortar andheated to 200 C. for 10 minutes in an Erlenmeyer flask on a pre-heatedoil bath. After cooling, the melt was heated with about 0.5%-arnmonia ona steam bath. The solution was filtered and the filtrate was acidified.The precipitate obtained was suction-filtered and taken up once more in0.5%-ammonia. After another acidification of the filtrate theprecipitate obtained was isolated by suction-filtration, dried andre-crystallized from methanol.

The N [4 (B 2-methoxy-S-chloro-benzamido ethyl) -benzenesulfonyl]-N-cyclopentyl-urea obtained was pentyl-urea so obtained was 183 185" C.

EXAMPLE l3 N-[4-( 3- 2-methoxy-5-chloro-benzamido -ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea 3.9 g. of sodium salt of 4-(,8-2-methoxy-5-chlorobenzamido -ethyl)-benzene-sulfonamide and 3.4 g. of N-acetyl N cyclopentyl-urea (M.P. 97-98 (3., prepared fromcyclopentyl-urea and acetoanhydride) were heated to 110 C. for 2 hoursin ml. of dimethylformamide. The solution obtained was concentratedunder reduced pressure to /3 of its volume and then Water andhydrochloric acid were added thereto. The solution was suctionfilteredand the residue was treated with 0.5-aqueous ammonia. After filtrationthe filtrate was acidified and the precipitate obtained was isolated bysuction-filtration, washed and dried. After recrystallization frommethanol, N [4-(,8- Z-methoxy-S-chloro-benzamido-ethyl)-benenesulfonyl]-N'-cyc1opentyl-urea was obtained having amelting point of 183-185 C.

EXAMPLE 14 N-[4(,6- Z-methoxy-S-chloro-benzamido -ethyl)-benzenesulfonyl]-N-cyclopentyl-urea 3.9 g. of sodium salt of 4-(B-2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonamide, 5.6 g. ofN,N-diphenyl-N'-cyclopentyl-urca (M.P. 137138 C., prepared from diphenylcarbamic acid chloride and cyclopentylamine) and 100 ml. ofdimethylformamide were heated to C. for 45 minutes. (After severalminutes a clear solution had formed). The solution was cooled, pouredinto water and then 0.5%-ammonia was added thereto. After filtration thefiltrate was acidified, the precipitate obtained was separated bysuction-filtration and introduced once fore into 0.5 %-ammonia. Afterfiltration and acidification of the filtrate a crystalline precipitateof N-[4-(fi- 2-methoxy 5 chloro-benzamido -ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea was obtained which, after drying andrecrystallization from methanol, was found to melt at 183-185 C.

EXAMPLE 15 N- [4- 3- 2-methoxy-5-chloro-benzamido -ethyl)benzenesulfonyl]-N'-cyc1openty1-urea 2 g. of sodium salt of 4-(l9-Z-methoxy-S-chloro-benzamido -ethyl)-benzenesulfonamide and 2.2 g. ofN,N- dicyclopentyl-urea (M.P. 248-249 C., prepared fromcyclopentyl-isocyanate and cyclopentyl-amine) were well mixed in amortar. The mixture was heated to 220 C. for 10 minutes in an Erlenmeyerflask on a pre-heated oil bath. After cooling, the sintered reactioncake was treated with 0.5 %-ammonia. After filtration, the filtrate wasacidified and a precipitate was obtained which was separated bysuction-filtration and dissolved once more in 0.5%- ammonia. Afterfiltration, the filtrate was acidified. The precipitate of crudeN-[4-(B- -methoxy-S-chloro-benzamido -ethy1)-benzenesulfonyl]-N-cyclopentyl-urea that had separated was isolated bysuction-filtration and dried. By treatment with methanol an at firstsmeary and then crystalline substance was obtained, which after suctionfiltration, was once more recrystallized from methanol. The meltingpoint of N[4-(5- 2-methoxy-5-chloro-benz amido -ethyl) -benzenesulfonyl]-N-cyclopentyl-urea obtained was 182-184" C.

9 EXAMPLE 16 N-[4-(B- 2-methoxy-S-chloro-benzamido -ethyl)-bcnzenesulfonyl] -N'-cyclopentyl-urea (a) Potassium salt of N-[4-(fi-2-methoxy-5-chlorobenzamido ethyl) benzenesulfonyl]-iminodithio-carbonic acid: 74 g. of 4-(B- 2-methoxy-5-chloro-benzamido-ethyl)-benzenesulfonamide were dissolved in 350 ml. ofdimethylformamide 23 g. of carbon disulfide and subsequently a solutionof 34 g. of potassium hydroxide in 50 ml. of water were added theretodropwise, while stirring. Stirring was continued for 3 hours at roomtemperature and the clear solution obtained was poured into 4 l. ofethanol. The potassium salt of N-[4-(/3- 2- methoxy chloro-benzamidoethyl) benzenesulfonyl]-irninodithio-carbonic acid which hadprecipitated was isolated by suction-filtration, washed with alcohol anddried. Yield 60 g.

(b) N- [4- 5- 2-methoxy-S-chloro-benzamido -ethyl benzenesulfonyl]iminodithio carbonic acid dimethyl ester: 36 g. of the potassium saltobtained according to (a) were dissolved in 60 ml. of l-normal sodiumhydroxide solution. While shaking, 12.6 g. of dimethyl sulfate wereadded to the clear solution, whereupon the temperature of the solutionrose. After standing for 30 minutes, the solution was decanted toseparate a semisolid smeary precipitation. After washing with water, thesmeary precipitate crystallized. The crystalline substance wasrecrystallized from dilute methanol, whereby 30 g. of N-[4 (B-2-methoxy-5-chloro-benzamido -ethyl)-benzenesulfonyl]-iminodithio-carbonic acid dimethyl ester, which wasfound to melt at 9496 C., were obtained.

(0) N-[4 (fit- 2 methoxy-S-chloro-benzamidoethyl)-benzenesulfonyl]-N'-cyclopentyl-isothio-urea methyl ether: 4.73g. of the ester obtained according to (b) were dissolved in 100 ml. ofdioxane. 0.85 g. of cyclopentylamine was added thereto and the Whole washeated on the steam bath for 1 /2 hours. After pouring into water andacidification with hydrochloric acid, the isothio-urea methyl etherindicated above was obtained as a smeary substance.

(d) N-[4 (ti- 2 methoxy-S-chloro-benzarnidoethyl)-benzenesulfonyl]-N'-cyclopentylurea: The smeary substanceobtained according to (c) was dissolved in dioxane, a 2-normal sodiumhydroxide solution was added thereto and the solution was heated for 1hour on the steam bath. After pouring into water and acidification withacetic acid, N-[4-(fl- 2-methoxy-S-chloro-benzamido-ethyl)-benzenesulfonyl] -N-cyclopentyl-urea was obtained as acrystallized precipitate. The substance was found to melt, afterrecrystallization from methanol, at 183185 C.

EXAMPLE 17 N- [4- (fi- 2-methoxy-5-chloro-benzamido -ethyl)-benzenesulfouyl]-N-cyclopentyl-urea (a) 4.9 g. of cyclopentyl-parabanicacid (M.P. 111- 112 C.) and 2.5 g. of triethylamine were dissolved in200 m1. of benzene and 8.9 g. of 4-(B 2-methoxy-5- chloro-benzamido-ethyl)-benzenesulfochloride (M.P. 102-103 C.) were added thereto. Themixture was refiuxed for 3 hours and the triethylamine hydrochlorideformed was separated while hot by suction-filtration. Petroleum etherwas added to the cooled filtrate and the crystals which precipitatedafter a short time were separated by suction-filtration. After thecrystals had been recrystallized two times from a mixture of methanoland dimethylformamide, the pure 1-[4-(,8- 2-ethoxy-5-chlorobenzamido-ethyl)-benzenesulfonyl] 3 cyclopentylparabanic acid, melting point18l-183 C., was obtained.

(b) 0.5 g. of the substance obtained according to (a) was heated with 5ml. of dioxane and 10 ml. of l-normal sodium hydroxide solution for 45minutes on the steam bath. Water was then added thereto, the mixture wasacidified and the precipitate obtained was recrystallized from methanol.The melting point of the N-[4-(B- 2-methoxy- 5 chloro-benzamido-ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea so obtained was 183-185 C.

EXAMPLE 18 N-[4 (5- 2-methoxy-5-chloro-benzamido -ethyl)-benbenesulfonyl]-N-cyclopentyl-urea.

(a) 3 g. of N-[4-(fi- 2-methoxy-5-chloro-benzamido-ethyl)-benzenesulfonyl] N cyclopentyl-thiourea (prepared from N-[4-(B-2-methoxy-5-chloro-benzamido -ethyl)-benzenesulfonyl]-N-phenyl-urea andcyclopentyl-amine, M.P. ISO-152 C.) were suspended in 50 ml. of Z-normalsodium hydroxide solution. Subsequently 10 ml. of 35% hydrogen peroxidewere added thereto and the whole was heated for 30 minutes on the steambath, acidified with dilute hydrochloric acid, the crystallineprecipitate was separated by suction-filtration and recrystallized frommethanol. The isolated N-[4-(B- 2-methoxy 5 chloro-benzamido-ethyl)-benzenesulfonyl]-N-cyclopentyl-urea was found to melt, afterrecrystallization from methanol, at 183-l85 C.

The same compound was obtained when the thiourea mentioned above wasdesulfurized by treating it with mercury-(II) oxide in the presence of asodium hydroxide solution. For this purpose 0.5 g. of the thiourea wasdissolved in 10 ml. of dioxane and 10 ml. of a 2-normal sodium hydroxidesolution. 0.22 g. of mercury oxide was added thereto and the whole wasstirred for 4 hours at 40 C. The mercury-(II) sulfide, which had formed,was removed by suction-filtration, the filtrate was acidified and theprecipitate of N-[4-(B- 2-methoxy-5-chlor@ benzamido-ethyl)-benzenesulfonyl] N cyclopentylurea obtained was separated bysuction-filtration and recrystallized from methanol. Melting point183185 C.

(b) 0.5 g. of N-[4-([3- Z-methoxy-S-chloro-benzamido-ethyl)-benzenesulfonyl] N cyclopentyl-thiourea was dissolved in 50 ml.of methanol. 0.22 g. of mercury-(II) oxide and a small amount of K 00were added thereto while stirring and the whole was heated to 50- 55 C.for 3 hours while stirring was continued. After removal by filtration ofthe mercury-(II) sulfide formed, the solution was concentrated whereuponthe N-[4-(3- 2-methoxy 5 chloro-benzamido-ethyl)-benzenesulfonyl]-N-cyclopentyl-isourea methyl ether was obtainedas a viscous resin. A sample of the above-mentioned isourea ether wascovered with concentrated hydrochloric acid in a test tube and, whilestirring, heated for several minutes on the steam bath. The crystallineproduct, constituting N- [4 (fl- 2 methoxy-S-chloro-benzamidoethyl)-benzenesulfonyl]-N'-cyclopentyl-urea was recrystallized frommethanol. M.P. 181-183 C.

EXAMPLE 19 N- [4- ,3- 2-ethoxy-5-chloro-benzamido -cthyl)benzenesulfonyl]-N'-cyclopentyl-urea 3.1 g. ofN-[4-(fi-arninoethyl)-benzenesulfonyl]-N'- cyclopentyl-urea (prepared bysaponification of N-[4-( 3- acetaminoethyl)-benzenesulfonyl] Ncyclopentyl-urea with sodium hydroxide solution) were suspended in 25ml. of chloroform. After addition of 1.6 g. of pyridine, 2.1 g. of2-methoxy-5-chlorobenzoic acid chloride were introduced and, whilestirring, the whole was heated to 40 C. for 6 hours. The solution thathad formed was concentrated in vacuo and the smeary residue wasextracted with 1%-ammonia. After acidification of the alkaline solutionand recrystallization from methanol, N- [4-(fi- 2-methoxy 5chloro-benzamido -ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea, meltingpoint 183- 185 C., was obtained.

mula

or a salt thereof of a pharmaceutieally acceptable base.

References Cited OTHER REFERENCES Derwent Belgian Patent Reports, No.5/67, section 3, p. 1 (1967).

UNITED STATES PATENTS 15 LEON ZITVER, Primary Examiner Loev 260-553 DWeber et a1. nu 260 553 DA G. A. SCHWARTZ, Asslstant Exammer Weber eta1. 260---553 DA (13 Cl Aumiiller et al. 260--S53 DA 2 999

